A homozygous<i>NOBOX</i>truncating variant causes defective transcriptional activation and leads to primary ovarian insufficiency

Li, Lin; Wang, Binbin; Zhang, Wei; Chen, Beili; Luo, Minna; Wang, Jing; Wang, Xi; Cao, Yunxia; Kee, Kehkooi

doi:10.1093/humrep/dew271

Cited by 41 publications

(37 citation statements)

References 29 publications

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“…Recently, NOBOX transcriptional targets in both humans and mice have been identified and include essential oocyte developmental factors such as growth differentiation factor 9 (GDF9) and octamer-binding transcription factor 4 (OCT4) (Choi & Rajkovic 2006, Bayne et al 2015. Additionally, a novel, loss-of-function NOBOX mutation was identified in a POI patient (Li et al 2017), providing further evidence of a key role for this gene in primordial follicle activation. These existing studies justify further investigation of the role that NOBOX has in human primordial follicles.…”

Section: R22mentioning

confidence: 82%

Advances in human primordial follicle activation and premature ovarian insufficiency

et al. 2020

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In women, the non-growing population of follicles that comprise the ovarian reserve is determined at birth and serves as the reservoir for future fertility. This reserve of dormant, primordial follicles and the mechanisms controlling their selective activation which constitute the committing step into folliculogenesis are essential for determining fertility outcomes in women. Much of the available data on the mechanisms responsible for primordial follicle activation focuses on a selection of key molecular pathways, studied primarily in animal models, with findings often not synonymous in humans. The excessive induction of primordial follicle activation may cause the development of premature ovarian insufficiency (POI), a condition characterised by menopause before age 40 years. POI affects 1–2% of all women and is accompanied by additional health risks. Therefore, it is critical to further our understanding of primordial follicle activation in order to diagnose, treat and prevent premature infertility. Research in primordial follicle activation has focused on connecting new molecules to already established key signalling pathways, such as phosphatidylinositol 3-Kinase (PI3K) and mammalian target of rapamycin (mTOR). Additionally, other aspects of the ovarian environment, such as the function of the extracellular matrix, in contributing to primordial follicle activation have gained traction. Clinical applications are examining replication of this extracellular environment through the construction of biological matrices mimicking the 3D ovary, to support follicular growth through to ovulation. This review outlines the importance of the events leading to the establishment of the ovarian reserve and highlights the fundamental factors known to influence primordial follicle activation in humans presenting new horizons for female infertility treatment.

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Section: R22mentioning

confidence: 82%

Advances in human primordial follicle activation and premature ovarian insufficiency

et al. 2020

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“…WES was performed as previously described (Li et al., ). Mutations meeting the following criteria were further analyzed: (1) missense, nonsense, frameshift, or splice site variation; and (2) novel or rare mutations (frequency <1% according to the prevalence of MMAF).…”

Section: Methodsmentioning

confidence: 99%

DNAH17 is associated with asthenozoospermia and multiple morphological abnormalities of sperm flagella

Sha

Wei

Ding

et al. 2019

Annals of Human Genetics

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Background Multiple morphological abnormalities of the sperm flagella (MMAF) is one kind of severe asthenozoospermia, which is caused by dysplastic development of sperm flagella. In our study, we sought to investigate the novel gene mutations leading to severe asthenozoospermia and MMAF. Methods and Materials The patient's spermatozoa were tested by Papanicolaou staining and transmission electron microscopy. Whole exome sequencing was performed on the patient with severe asthenozoospermia and MMAF. Sanger sequencing verified the mutations in the family. The expression of DNAH17 was detected by immunofluorescence and Western blot. Results Spermatozoa sample from the patient showed severe asthenozoospermia and MMAF. We detected biallelic mutations (c.C4445T, p.A1482V and c.C6857T, and p.S2286L) in DNAH17 (MIM:610063). The protein expression of DNAH17 was almost undetectable in spermatozoa from the patient with the biallelic mutations. Conclusion These results demonstrated that DNAH17 may be involved in severe asthenozoospermia and MMAF.

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“…A recent study on whole-exome sequencing of Chinese POI patients showed a novel homozygous truncating variant in the NOBOX gene (chr7:144098161delC) that impaired severely the transcriptional activation of the GDF9 gene in functional analyses, suggesting that a loss-of-function effect on NOBOX transcriptional activity could be associated with POI via reduced GDF9 (Li et al, 2017). …”

Section: Gdf9 and Bmp15 In Dizygotic Twinning Poi And Pcosmentioning

confidence: 99%

Molecular Aspects and Clinical Relevance of GDF9 and BMP15 in Ovarian Function

Belli

Shimasaki

2018

Vitamins and Hormones

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Growth and differentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15) are oocyte-secreted factors with a leading role in the control of ovarian function in female reproduction, modulating both the cell fate of the somatic granulosa cells and the quality and developmental competence of the egg. This short review aims to consolidate the molecular aspects of GDF9 and BMP15 and their integral actions in female fertility to understand particularly their effects on oocyte quality and fetal growth. The significant consequences of mutations in the GDF9 and BMP15 genes in women with dizygotic twins as well as the clinical relevance of these oocyte factors in the pathogenesis of primary ovarian insufficiency and polycystic ovary syndrome are also addressed.

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A homozygousNOBOXtruncating variant causes defective transcriptional activation and leads to primary ovarian insufficiency

Cited by 41 publications

References 29 publications

Advances in human primordial follicle activation and premature ovarian insufficiency

Advances in human primordial follicle activation and premature ovarian insufficiency

DNAH17 is associated with asthenozoospermia and multiple morphological abnormalities of sperm flagella

Molecular Aspects and Clinical Relevance of GDF9 and BMP15 in Ovarian Function

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